Delivery of pharmaceutical agents incorporated in topical drug formulations often proves difficult. Oily materials such as petrolatum are commonly used as the base in topical skin care formulations to prevent moisture loss from skin. However, a number of pharmaceutical agents are difficult to administer topically because they are either incompatible with the oily base material, or else poorly absorbed in the skin. In either case, such incompatible pharmaceutically active drug tends to slowly crystallize and precipitate out of the oil-based or water-based formulation. Such crystallization and precipitation of the active drug results in reduced effectiveness of the drug to the skin. An additional drawback of oil-based topical formulations is that they are often deleteriously greasy for convenient usage.
Delivery of poorly soluble orally administered drugs is lowered due to similar difficulties. The delivery of water insoluble drugs at an absorption site in the gastrointestinal tract is low partly due to insolubility of the drug in the aqueous gastric environment.
Aqueous emulsions employing food grade or pharmaceutical grade polar lipids as emulsifiers have been used as vehicles to deliver both water insoluble drugs and oil-incompatible drugs. For instance, U.S. Pat. No. 4,346,086 discloses a topical cream formulation containing fatty acid sorbitan ester, fatty acid monoglyceride, beeswax, liquid paraffin, petroleum jelly, and water as a delivery vehicle for anti-inflammatory steroids. As a further example, JP 04,224,507 discloses a transparent gel composition having appropriate fluidity and softness for skin cleansing applications. The composition includes a) one or more hydrophilic surfactants of polyoxyethylene sorbitol fatty acid esters, b) polyoxyethylene glycerol fatty acid esters and one or more lipophilic surfactants of mono-and diesters of diglycerol with branched or unsaturated fatty acids, c) polyhydric alcohol, d) liquid or paste oil ingredient(s), and e) water. These two topical drug delivery vehicles are undesirably complex, both with regards to composition as well as in method of preparation.
SU 514,588 discloses that a mixture of monoglyceride, acetylated monoglyceride, gelling agent, and glycerin displays film-forming properties when present in a very low concentration aqueous solution. Disclosed is a composition of 0.5-5 weight percent gelling agent, 1-3 weight percent acetylated monoglyceride, 0.5-1 weight percent monoglyceride, 1-3 weight percent glycerin, with the balance being water. A thin coating of this liquid composition forms a solid film on fruit under ventilation.
An alternative type of drug delivery system is a binary composition formed from a monoglyceride lipid and water. It is known that such binary monoglyceride-water systems form liquid crystalline gel phases in the useful drug delivery temperature range of about 20 to about 40.degree. C. Liquid crystalline phases are commonly divided into the three main categories of lamellar, hexagonal, and cubic phases. All three liquid crystalline phases may be formed in a monoglyceride-water binary system in the temperature range of about 20 to about 40.degree. C.
Binary monoglyceride-water liquid crystalline phase compositions have been researched for use as sustained-release drug carriers. For example, see Larson, K. Cubic Lipid-Water Phases: Structures and Biomembrane Aspects. Journal of Physical Chemistry, Vol 93 (1989), pp. 7304-7314. Liquid crystalline systems act as sustained release drug emulsifiers due to the physical liquid crystalline structure. Specifically, a binary lamellar phase system exists as a one-dimensional sandwich-type structure having alternating layers of lipid and water. A binary hexagonal phase is periodic in two dimensions. A binary cubic phase liquid crystalline system is a periodic curved bilayer extending in three dimensions, separating two congruent networks of water channels. A fully swelled cubic phase (having about 50 weight percent water) is highly viscous and has a water pore diameter for receiving active agents of up to about 5 nm. When formed from food- or pharmaceutical-grade monoglycerides, these physical properties make binary liquid crystalline phase compositions in situ-forming biodegradable matrix systems. The particular liquid crystalline phase(s) formed by a binary monoglyceride-water composition is dependent upon the ratio of monoglyceride to water, and temperature. Liquid crystalline phase diagrams of binary compositions of 1-monoglycerides in water are illustrated by Krog, Riisom, and Larsson, in "Applications in the Food Industry: I", Encyclopedia of Emulsion Technology, Vol. 2. (1985) N.Y., Marcel Dekker, Inc., pp. 327-329, incorporated herein by reference.
The drug delivery effectiveness of a binary monoglyceride-water liquid crystalline phase composition is partly determined by the weight ratio of monoglyceride to water. Binary liquid crystalline phase systems are categorized as having either a relatively high or low water content. A "high water content" binary monoglyceride-water composition having a weight ratio of from about 1:1 to about 4:1 monoglyceride to water is well suited for delivering either water-soluble or lipid-soluble drugs. A "low water content" binary monoglyceride-water composition having a weight ratio greater than about 4:1 monoglyceride to water is well suited for delivering water-insoluble drugs. A useful liquid crystalline phase drug delivery composition should be homogeneous. A binary composition having a weight ratio less than about 1:1 monoglyceride to water is not useful because it deleteriously separates into aqueous and liquid crystalline phases.
Engstrom found that the highly ordered structure of binary monoglyceride-water cubic phase compositions makes cubic liquid crystalline phase compositions very useful in drug delivery, due to the fact that they have very prominent lipid and water domains, which may solubilize both water- and lipid-soluble substances, as well as molecules with pronounced amphiphilic characters. Engstrom, S. Drug Delivery from Cubic and other Lipid-Water Phases, Lipid Technology, Vol. 2, no. 2 (April 1990), pp. 42-45. However, the high viscosity (greater than 2 M cPs) and stiffness of a binary monoglyceride-water cubic phase having a high water content is deleteriously limiting for topical and oral gel delivery applications. Such high viscosity compositions are difficult to process, as well as being difficult to extend and spread during topical application. For that reason, Engstrom's research was directed towards developing methods for forming aqueous dispersions of the binary monoglyceride-water cubic phase for oral delivery.
Within the pertinent drug delivery temperature range of about 20 to about 40.degree. C., the viscosity of a binary monoglyceride-water liquid crystalline system having relatively low water content (ratio of at least 4:1 weight of monoglyceride to water) is too low for use as a topical gel. The desired viscosity for a topical formulation is from about 20 to about 12,000 cPs. Gel formation occurs at a viscosity of about 500 cPs. Gel formation is an important property for drug delivery vehicles used to topically or orally deliver many difficult-to-deliver drugs. Gel formation of the vehicle helps prevent crystallization and precipitation of the water-insoluble and lipid-incompatible drugs that would benefit the most from delivery by an emulsion-type vehicle.
In light of the above, it would be desirable to provide a liquid crystalline phase drug delivery vehicle for both topical and oral drug delivery having a viscosity high enough to form a gel, yet low enough to be easily processable and extendable, in the temperature range of about 20 to about 40.degree. C. It would be further desirable for such liquid crystalline composition to include both high and low water content formulations for usefulness in the delivery of drugs having a broad solubility range. It would be even further desirable for such composition to be relatively simple, both with regards to composition as well as in method of preparation.